Desmopressin (1-desamino-8-D-arginine vasopressin, dDAVP®) is an analogue of vasopressin. Desmopressin has decreased vasopressor activity and increased anti-diuretic activity compared to vasopressin. This pharmacological profile enables desmopressin to be used clinically for anti-diuresis without causing significant increases in blood pressure. Desmopressin is commercially available as the acetate salt both in tablet form and as a nasal spray, and is commonly prescribed for primary nocturnal enuresis (PNE) and central diabetes insipidus. Commercially available dosage forms have not been approved for use to treat nocturia, voiding postponement, or incontinence.
Desmopressin has been administered intravenously, subcutaneously, intranasally, and orally. The intravenous route of administration is clinically used almost exclusively to treat patients with mild hemophilia or Von Willebrand's Disease to raise blood levels of Factor VIII prior to surgery. Subcutaneous injection is used infrequently and primarily in patients with central diabetes insipidus, a deficiency of endogenous vasopressin resulting in the renal production of large volumes of extremely dilute urine which can cause severe dehydration. Intranasal administration of desmopressin via a nasal spray is approved for the maintenance treatment of patients with central diabetes insipidus and in children (ages 6 to 16 years) with primary nocturnal enuresis. An oral tablet dosage form of desmopressin has also been approved for the treatment of central diabetes insipidus and primary nocturnal enuresis.
A major drawback of subcutaneous injection is that it is a difficult and uncomfortable procedure, resulting in poor patient compliance, especially in children. While oral or nasal routes of administration are more convenient they produce low and variable bioavailabilities of 0.1% for oral and 3.4% for nasal with 10 to 20 fold ranges for peak blood levels. Desmopressin, an 1183 Da molecule, is usually dosed at 10 to 20 micrograms (μg) for nasal and 100 to 400 μg for oral administration.
Currently, approved labeling for desmopressin recommends dosing in the following ranges depending on the clinical indication and the route of administration:
Route ofAdministrationClinical Indication(% Bioavailability)Dose Range (daily)Hemophilia/VonIntravenous (100)0.3 mcg/kg (21 mcg for 70 kgWillebrand'spatients)Central DiabetesIntravenous (100)2-4 mcg qd or 1-2 mcg bidInsipidus (CDI)Subcutaneous (±90)2-4 mcg qd or 1-2 mcg bidIntranasal (3-5)5-40 mcg qd or 5-20 mcg bidOral (0.1)100-600 mcg bidPrimary NocturnalIntranasal (3-5)10-40 mcg qhsEnuresis (PNE)Oral (0.1)200-600 mcg qhs
The average maximum plasma/serum concentrations achieved (Cmax) with a typical intranasal dose (20 μg, 10 μg in each nostril) of desmopressin for central diabetes insipidus (CDI) or PNE is approximately 20-30 pg/ml, based on 3-5% bioavailability. For the desmopressin oral tablet with only 0.1-0.15% bioavailability, a standard dose of 200-400 μg would also produce an average peak plasma/plasma/serum level of 20-30 pg/ml. (Bioavailability varies widely from person to person.)
While existing formulations of desmopressin have proven to be adequate for many patients when used for these clinical indications, variable efficacy and occasional hyponatremia continue to be problems related to the aforementioned variability. Tablets are often preferred by patients because of their ease of use, discretion and the lack of uncertainty of correct administration. However, tablets generally need to be taken with a glass of water or other drink, which is a problem, since fluid intake needs to be restricted in connection with desmopressin treatment; and the message to the patient is much clearer when there is no water intake at all. In addition, while the above doses and plasma/serum concentrations are effective for treating CDI and PNE, standard dosages of desmopressin have been shown to cause undesirable side-effects including high incidences of hyponatremia.
In fact, the U.S. Food & Drug Administration recently warned physicians and the public that “[c]ertain patients, including children treated with the intranasal formulation of [desmopressin acetate] for primary nocturnal enuresis (PNE), are at risk for developing severe hyponatremia that can result in seizures or death.”